Cancer And Tumor Predisposition Syndromes

Front 1

Von Hippel Lindau Gene

Back 1

VHL

Front 2

VHL inheritance

Back 2

AD

Front 3

VHL - how much inherited how much de novo

Back 3

80% inherited

20% de novo

Front 4

Mean age of dx in VHL

Back 4

25y

Front 5

Common features of VHL

Back 5

hemangioblastoma (most common)

retinal hemangioma - can cause vision loss, start screening at 5 years

cerebellar hemangioma - can cause balance, speech, extremity issues

spinal hemangioma - cord compression, extremity issues

endolympathic sac tumor

epidydimal cysts

pancreatic cysts

pheos - benign tumor of adrenal gland

renal cancers (clear cell)

Front 6

What percent of thyroid cancers are MTC?

Back 6

10%

Front 7

What is the most common type of thyroid cancer?

Back 7

85 - 90% well differentiated

of those 90% papillary

Front 8

What percent of thyroid cancer is follicular?

Back 8

10%

Front 9

What percent of MTC is sporadic?

Back 9

75%

Front 10

What percent of MTC is due to MEN2A? FMTC? MEN2B?

Back 10

21% MEN2A

2% FMTC

2% MEN2B

Front 11

What gene and chr for MEN2?

Back 11

RET - proto oncogene; mutation leads to gain of function --> tumorigenesis

chr 10

AD with very few new mutations

Front 12

What are the risks for MEN2?

Back 12

MTC - 100% lifetime risk

Pheo 50%

Hyperparathyroidism 10-20%

c-cell hyperplasia is very indicative of MEN2!

Front 13

What are the features of MEN2?

Back 13

Aggressive MTC that can occur in childhood

Thyroidectomy rec in first few months of life

mucosal neuroma

50% risk for pheo

skeletal abnormalities

marfanoid appearance

usually de novo

Front 14

What are the tumors associated with MEN1?

Back 14

Varying concentration of >20 endocrine and non-endocrine tumors

Parathyroid tumors or enlargement

Hyperparathyroidism

Hypercalcemia·

90% by 20-25y

100% by 50y

Other tumors

Pituitary

Gastro-entero-pancreatic tract

Carcinoid

adrenocortical

Front 15

What are the non endocrine tumors of MEN1

Back 15

facial angiofibromas

collagenomas

lipomas

meningiomas

epindymomas

leiomyomas

Front 16

What gene associated with BHD?

Back 16

FLCN

AD

Front 17

What is the pathology of BHD renal tumors?

Back 17

Chromophobe, mixed oncocytic

Front 18

What other findings with BHD?

Back 18

skin - fibrofolliculomas (pathognomonic)

pneumothorax - 90%

Front 19

Gene associated with HLRCC?

Back 19

FH

Front 20

What type of renal cancer pathology with HLRCC?

Back 20

papillary?

Front 21

What percent with HLRCC have renal cancer?

Back 21

10-60%

Front 22

What genes associated with TSC?

Back 22

TSC1

TSC2

Familial 50/50 either gene

Simplex 80-85% TSC2

Front 23

What is the de novo rate for NF?

Back 23

50%

Front 24

VHL screening

Back 24

annual brain and full spine MRi

opthal exam annually

annual/semi-annual abdominal MRI

biochemical screening for pheos starting at age 5

Front 25

Features associated with MEN2B

Back 25

MTC is very aggressive can occur in early childhood

thyroidectomy rec in first few months of life

mucosal neuromas

neuroma of eyelids

ganglioneuromas

GI tract - disturbance of colonic function

Marfanoid appearance

usually de novo

Front 26

What does RET testing look like in MEN2?

Back 26

Labs may not routinely sequence all exons -- just exons 10, 11, 130-16

95% DR in proband

Front 27

What do pheos in MEN2 look like?

Back 27

bilateral (65%), adrenal predominantly (99%)

mean age of dx in mid 30s

rarely malignant

can screen annually with plasma metanephrines, age depends on mutation

Front 28

What is the gene for MEN1?

Back 28

menin1/MEN1

Front 29

What is the clinical diagnostic criteria for MEN1?

Back 29

present of at least 2 of the 3:

parathyroid tumors

pituitary tumors

GEP tumors

Front 30

Hereditary Pheo/Paras

Back 30

Adrenal medulla

sympathetic paraganglioma

parasympathetic paraganglioma

Front 31

What percent of PGL/pheos have an identifiable mutation?

Back 31

25-50%

Front 32

What are the genes associated with hereditary para/pheos?

Back 32

SDHD (daddy) - imprinted; only at risk if inherited from father

head, neck, adrenal, extra adrenal

SDHB - extra adrenal, head/neck, adrenal

fewer tumors per person but greater chance for malignancy

increased renal cancer risk

AD penetrance likely 75-80%

Front 33

What are the biochemical testing patterns assocaited with VHL, RET, SDHX?

Back 33

elevated norepinephrine - VHL

elevated metanephrine - RET

Mixed - NF, sporadic, or SDHX

Front 34

What are leiomyomas?

Back 34

uterine fibroids, require early hysterectomies

Front 35

What are the features of TSC?

Back 35

skin - hypomelanotic macules, facial angiofibromas, shagreen patches, collagenomas, ungual fibromas

brain - cortical tubers, subependymal nodules, giant cells astrocytomas, seizures, learning diffs

renal - angiomyolipomas, cysts

cardiac - rhabdomyomas

lung - LAM

Front 36

What percent of TSC is familial? sporadic?

Back 36

30% familial

70% sporadic

Front 37

What percent have a mutation in TSC1? What percent in TSC2?

Back 37

familial - 50% tsc1, 50% tsc2

sporadic - 15-20% tsc1, 80-85% tsc2

Front 38

What gene is FAMMM associated with?

Back 38

CDKN2A

CDK4

AD with incomplete penetrance

Front 39

What else is associated with FAMMM?

Back 39

pancreatic cancer, varies depending on which mutation

Front 40

What are the features of Gorlin syndrome?

Back 40

calcification of the falx

jaw keratocyst

palmar/plantar pits

multiple (>5) BCCs in a lifetime, BCC before 30 years of age

Front 41

What gene is associated with Gorlin?

Back 41

PTCH1

Front 42

What is the tumor most associated with NF2?

Back 42

bilateral vestibular schwannomas

Front 43

what other features associated with NF2?

Back 43

meningioma, glioma, neuropathy (facial palsy, foot drop), cataracts, skin schwannomas

Front 44

What is the inheritance patter for xeroderma pigmentosum?

Back 44

AR; mutations identified in about 50% of patients

Front 45

What are the features of XP?

Back 45

extreme photosensitivity, defective nucleotide excision repair, premature skin aging

first skin cancers dxed in first few years of life

opthal and neuro issues as well

Front 46

What are the features of ataxia telangiectasia?

Back 46

immunodef

progressive cerebellar ataxia starting at 1-4y

telangiectasias in eyes

increased sensitivity to radiation, increased risk for leukemia, lymphoma

Front 47

What are the features associated with Fanconi Anemia?

Back 47

physical manifestation in 60-75%

short stature, pigmentation, radial formations

progressive bone marrow failure

sold tumors in head/neck esophagus, cervix, liver

AR

Front 48

What other tumors are those with RB mutations at risk for?

Back 48

pineal or neuroectodermal tumors of the brain

osteosarcomas

soft tissue sarcomas

melanoma

these may present in adolescence or adulthood

risk increased in those who receive high dose external beam radiation

Front 49

What features in PJS associated with?

Back 49

GI hamartomas - frond-like/brocolli stalks

characteristic blue/black pigmentation around mouth, toes, may fade after puberty

small bowel, ovary, sex cord tumors, pancreatic cancers, lung cancer

Front 50

What gene with PJS?

Back 50

STK11

Front 51

What many tumors and where in PJS?

Back 51

<100 hamartomatous GI polyps in stomach to rectum (most commonly in small intestine)

symptoms begin <20 years

Front 52

What genes cause JPS?

Back 52

AD, BMPR1A and SMADH4

Front 53

What types of polyps in JPS?

Back 53

hamartomatous or mixed adenomatous

can occur anywhere in the GI tract

should be considered in anyone with >3 juvenile polyps

Front 54

What are the cancer risks with JPS?

Back 54

Colon - 39%

gastric - 21% with gastric polyps

small bowel

some with SMAD4 muts have JP and HHT

Front 55

What gene is HDGC associated with?

Back 55

CDH1

Front 56

What is the risk for gastric cancer?

Back 56

>70%